Organocatalytic Enantioselective Michael-Addition of Malonic Acid Half-Thioesters to beta-Nitroolefins: From Mimicry of Polyketide Synthases to Scalable Synthesis of gamma-Amino Acids

Abstract

Highly enantioselective biomimetic Michael addition reactions of malonic acid half thioesters (MAHTs) to a variety of nitroolefins, affording the optically active gamma-amino acid precursors, were developed by employing the Cinchona-based squaramides (up to > 99% ee). Remarkably, this biomimetic process is enantioconvergent, a highly desirable feature of a catalytic asymmetric reaction, whereby E/Z-isomers of the nitroolefins afford the same product enantiomer. The synthetic utility of this organocatalytic protocol was also demonstrated in the formal synthesis of pharmaceutically important gamma-amino acids such as baclofen. Moreover, a quantum chemical analysis of the catalyst-substrate complexes is shown to give a detailed and instrumental insight into the origin of the observed catalytic activity.